From IgE to Anti-IgE: Where do we stand?

Authors


Eckard Hamelmann, MD
Klinik für Pädiatrie m.S. Pneumologie und Immunologie
Charité
Humboldt-Universität
Augustenburger Platz 1
D-13353 Berlin
Germany

Abbreviations: 
BDP

Beclomethasone diproprionate

FEV1

forced expiratory volume in 1 second

ICS

inhaled corticosteroids

iv

intravenous

PAF

platelet activating factor

PEF

peak expiratory flow

QOL

Quality of life

rhuMAb

recombinant humanized monoclonal antibody

SAR

seasonal allergic rhinitis; sc: subcutaneous

SIT

specific immunotherapy.

Allergy and IgE – a pair of shoes. The term “allergy” was originally introduced by von Pirquet in 1906 meaning “changed reactivity” of a host after the second or subsequent contact with an “agent”. The clinical features of this hypersensitivity reaction comprise asthma, hay fever, urticaria and eczema, and were originally termed “atopy” by Coca and Cooke in 1923. The first implication of a transferable/soluble factor as the mediator of an allergic reaction was published in 1919. In this case report, Ramirez describes a man who experienced an acute asthmatic episode while entering a horse-drawn coach in New York's Central Park two weeks after having received a 600-ml blood transfusion from a man with a known horse allergy (1). The first scientific description of the mechanism of the allergic reaction was provided in 1921 by Prausnitz and Küster, who showed that a serum factor (“reagin”) was able to passively transfer hypersensitivity reactions from an allergic to the skin of a non-allergic patient (2). But only after another forty-five years could Ishizaka and colleagues (3, 4) and Johannson and colleagues (5) independently show that this “reagin” was a novel class of serum antibodies – immunoglobulin-E: IgE (6). Now, another 35 years later, we stand on the brink of a novel therapeutic option for the treatment of allergic diseases, by directly targeting increased serum IgE with antagonizing antibodies: anti-IgE antibodies.

The prevalence of asthma, hay fever and other IgE-mediated diseases (7) has increased dramatically in industrialized countries over the last decades, making allergies a very serious public health problem (8–10). Asthma prevalence rates increased by 75% in the Unites States between 1980 and 1994 (11). The prevalence of allergic diseases is even higher in children (12), where asthma is the most common chronic illness overall. Twenty-three percent of British children aged 6–7 years, and 21% of British children aged 12–14 years (13) suffer from asthma. Despite better understanding of pathophysiology and improved treatment protocols for allergic diseases, overall morbidity and even mortality rates of asthma have increased in the last two decades (14). The most robust predisposing factor for the development of allergic diseases is atopy, the genetic predisposition to produce allergen-specific IgE (15).

I.Role of IgE in allergic diseases

IgE, similar to other immunoglobulins, is comprised of two heavy and two light chains (Fig. 1). It is produced by allergen-specific plasma cells after isotype switch to the epsilon-chain. IgE production is mainly under the control of T cells and T-cell cytokines (Fig. 2) (16, 17). In the case of allergic immune reactions, naive T cells develop towards the so-called Th2-type, defined by the predominant production of Th2-cytokines, especially IL-4, IL-5 and IL-13 (18). Differentiation of B cells to IgE-producing plasma cells requires two distinct signals, the first provided by IL-4 and IL-13 (19, 20), the second by interaction between the co-stimulatory antigen CD40 on the surface of B cells with CD40-ligand on T-cell surfaces (21, 22).

Biological activities of IgE are mediated through specific receptors, of which the high-affinity receptor (FcεRI) is mainly expressed on mast cells and basophils (23, 24), whereas the low-affinity receptor (FcεRII, CD23) is expressed on B cells (25, 26). Whereas free serum IgE has a very short half-life of about two and a half days, mast cells remain sensitized for up to 12 weeks following binding of IgE to high-affinity receptors.

Re-exposure of sensitized patients with allergen leads to binding of specific allergen to IgE–FcεRI complexes on mast cells. This activates the allergic cascade characteristic for the early IgE-mediated reaction (27, 28) (Figs 2 and 3). The cross-linking of receptors immediately triggers the release and production of preformed and newly synthesized mediators, such as leukotriens, prostaglandins, cytokines and chemokines. These pro-inflammatory mediators cause, depending on the site of allergen exposure, immediate reactions such as airway smooth muscle contraction, mucus hypersecretion, mucosal oedema of upper or lower airways, or conjunctivitis. The finding that human mast cells, after IgE-mediated activation, produce a wide range of cytokines (29, 30), suggests that IgE may contribute to subsequent inflammatory reaction such as airway eosinophilia and airway remodelling associated with the late allergic response.

Two recent epidemiological studies from the same group suggest a close correlation between IgE serum levels and the presence or severity of asthma (31, 32). Childhood asthma is mainly found in patients who are atopic and sensitized to common environmental allergens, such as house dust mites, tree and grass pollens (33, 34). Moreover, persistent wheezing and early sensitization are both associated with high total IgE serum levels in children at all age (34). Although increased levels of total IgE have been reported to be associated with prevalence of asthma even in non-atopic subjects that do not produce specific IgE to common allergens (32), other studies have not found such a link (5). Many non-specific factors such as infections and air pollutants are known to have a mitogenic effect and stimulate a polyclonal IgE production (7). In contrast, patients with a non-allergic asthma have negative skin tests to common allergens and normal total IgE serum levels. They represent about 50% of adult and 20–30% of childhood asthma. Patients with this non-allergic asthma tend to have a more severe disease, but clearly show signs of a similar inflammatory response in the airways as observed in patients with allergic asthmatic (35). Interestingly, in patients of the non-allergic group, a significant local IgE production in the airways has recently been described (36), indicating that IgE may also play a role in asthma pathogenesis for this subset (37). The association with increased IgE serum levels is also obvious for other allergic diseases such as seasonal allergic rhinitis (SAR), insect venom allergy or food allergies. The serum levels of IgE antibodies to cow's milk and hen's egg predict the probability of a positive outcome (an allergic reaction) of food challenges in children (38, 39).

Despite the growing understanding of the pathophysiology of allergic diseases, current treatment today is unspecific and intervenes at a late stage of the allergic cascade (e.g., antihistamines, beta-2-agonists, topical and systemic corticosteroids, and chromones) (40). The only treatment option with a curative approach is allergen-specific immunotherapy (SIT), with restrictions in regard to polyzensitized patients, patients suffering from “atopic dermatitis”, i.e., the IgE-associated subgroup of AEDS (7), and very young patients (41, 42). New treatment options are therefore required, that target the pathophysiological cascade of allergen-mediated immune reactions earlier and in a more general way (43,44). Because of the pivotal role of IgE, antagonizing or inhibiting IgE responses directly by anti-IgE antibodies provides a novel and promising approach to treat allergic diseases (45–47).

II. Anti-IgE for the treatment of allergic diseases

(1) Mechanism of Anti-IgE

The binding site of IgE for the high-affinity receptor FcεRI is located within the third domain of the heavy chain, Cε3 (Fig. 1) (48). A murine antibody, MAE1, was generated, that recognizes the same residues in the Cε3 domain of IgE that are responsible for binding to FcεRI (49). To avoid sensitization with foreign proteins, a humanized version, containing 95% of a human IgG1 antibody and only 5% of the murine IgE-specific epitope, was constructed and named recombined humanized monoclonal antibody (rhuMAb)-E25 or omalizumab (50).

  • The main features of anti-IgE are that it:

  • 1recognizes and binds serum IgE, but not IgG or IgA;
  • 2inhibits the binding of IgE to FcεRI;
  • 3does not bind to IgE bound to mast-cells or basophils, and thus does not cause degranulation (“non-anaphylactic antibody”);
  • 4blocks mast cell degranulation following passive sensitization in vitro or challenge with allergen in vivo ;
  • 5is unspecific for the allergen-specificity of the IgE antibody, meaning that it binds to any IgE molecule.

(2) Safety, tolerability, route of administration

A series of preclinical and phase I studies were conducted to test safety and efficacy of anti-IgE. Studies in cynomolgus monkeys showed that anti-IgE binds IgE resulting in the formation of small (c. 1000 kDa), non-precipitating and non-complement-activating immune complexes that are no longer able to bind IgE-receptors. E25 was most concentrated in the serum compartment, no specific organ deposition was observed, and immune complexes were eliminated by urinary excretion (51).

In addition to the effect on circulating IgE, treatment with anti-IgE also suppressed IgE-receptor expression in basophils in vitro (52), supporting that IgE receptor expression is regulated by and associated with IgE serum levels.

Single- and multi-dose trials in adults with and without allergic disease showed that anti-IgE was well tolerated and caused a decrease of IgE serum levels in a dose-dependent manner as soon as 5 min after intravenous and within 24 h after subcutaneous injections (53, 54). The decrease of IgE lasted, depending on the antibody dose, for about 4–6 weeks after a single injection with anti-IgE.

In a large phase II study in adults with SAR (55), sc vs. iv treatment at different dosages (0.15 mg/kg body weight sc, 0.15 mg/kg iv, or 0.5 mg/kg iv, seven injections within 84 days) were compared. Pharmacodynamics between the sc and iv routes of administration did not differ. Anti-IgE decreased serum IgE levels in a dose- and baseline IgE-dependent fashion (Fig. 4).

Not all routes of administration of anti-IgE are similarly effective. Fahy et al. found that aerosolized anti-IgE in patients with mild allergic asthma did not significantly suppress serum IgE levels and did not, despite detectable levels of omaliumab, affect the early asthmatic response to the allergen (56).

In summary, the data show that anti-IgE is a safe and well tolerated drug that can effectively reduce serum IgE levels.

(3) Anti-IgE and asthma

Treatment of asthma has substantially improved over the last decades. Inhaled steroids (ICS) are the standard anti-inflammatory medication and normally effectively control symptoms of mild to moderate asthma. Some patients, however, with moderate to severe asthma, remain symptomatic even under persistent treatment with ICS, and sometimes are in need for systemic steroids to control the disease. New treatment options more specifically targeting the pathophysiological events causing development of asthma are therefore required for this patient group, of which anti-IgE treatment is one possible candidate.

Effects of anti-IgE on early and late-phase allergic responses (Phase I/II studies) Two studies were performed in patients with mild asthma to test the ability of anti-IgE to inhibit early and late-phase allergic responses after bronchial challenge with allergen (57, 58).

Study design : Randomized, double-blind, placebo-controlled, parallel-group study.

Patients : 11 ( 57 ) and 19 ( 58 ) adults, respectively, with mild asthma.

Medication : Anti-IgE was administered intravenously at a dose of 2 mg/kg body weight on day 0 and at a dose of 1 mg/kg on days 7, 14, 28, 42, 56, and 70.

Primary outcome : Provocative dose of inhaled allergen needed to cause a 15% fall in FEV1 (PC15) after bronchial allergen challenge.

Results : Anti-IgE treatment significantly decreased IgE serum levels and reduced the early allergic response, as demonstrated by a significantly smaller reduction in FEV1 and a significant increase in median allergen PC15 after allergen challenge on days 27, 55, and 77 ( 57 ). A similar effect was observed for the late-phase response to allergen, assessed 2–7 h after allergen provocation ( 58 ). Interestingly, anti-IgE treatment significantly reduced the rise in sputum eosinophils following allergen challenge, an inflammatory reaction linked to the development of the late asthmatic response. No improvement of unspecific hyperresponsiveness, asthma symptom score and overall lung function was shown after treatment with anti-IgE, compared to placebo. Still, the studies demonstrated that intravenous or subcutaneous administration of anti-IgE is able to reduce early and late-phase allergic responses in patients with asthma.

Effects of anti-IgE on asthma symptom scores (Phase II study) The promising results of the early studies had to be confirmed in a large-scale study investigating the efficacy of anti-IgE in the treatment of asthma. Dosage was adapted to individual body weight and serum IgE levels to ensure a constant ratio of IgE to anti-IgE antibody. Administration was by the iv route (59).

Study design : Multi-centre, randomized, double-blind, parallel-group, placebo-controlled study.

Patients : 317 adolescent and adult patients (11–50, mean 30 years) with moderate to severe persistent allergic asthma and requirement for daily inhaled or oral ( n  = 35) steroids.

Medication : Anti-IgE iv at a dose of 2.5 (low dose) or 5.8 (high dose) µg/kg body weight/ng serum IgE on days 0 and 4 (half dose) and on day 7 and in biweekly intervals for 20 weeks (full dose). Stable steroid medication for first 12 weeks, tapering of steroid dosages during last 8 weeks.

Primary outcome : Asthma symptom scores (daily symptom diary, max. score 7).

Secondary outcomes : Steroid/, beta-2-agonist use, PEF, FEV1, asthma exacerbation.

Results : Treatment with anti-IgE led to a fast decrease in serum IgE levels, which remained stable and less than 5% of mean baseline values for 20 weeks. Following treatment with the low or high dose of anti-IgE, the proportion of patients at 12 weeks with at least a 50% reduction in asthma symptom scores was significantly higher than in the placebo group (49% and 47% vs. 24%, P  < 0.001). The mean reduction of symptom scores from mean baseline score 4.0 for all patients was significantly higher in both the low- (2.8) and the high dose (2.8) anti-IgE group, compared to the placebo (3.1), although patients in the placebo also enhanced during the course of the study ( 59 ).

The requirements for inhaled or oral steroids were reduced in patients treated with anti-IgE: 78% of patients receiving the high dose (P = 0.04) and 57% of the low-dose group (P = 0.23, n.s.) had at least a 50% reduction in overall steroids after 20 weeks, compared to 33% of patients receiving the placebo. The decrease in oral or inhaled steroid medications was associated with a decrease of beta-2-agonist use by 1.8 puffs/day in the high-dose anti-IgE group (P = 0.02) and by 1.2 puffs/day in the low-dose anti-IgE group (P = 0.24) compared with 0.8 puff/day in the placebo group (59).

Treatment with anti-IgE increased morning PEF at 12 weeks, compared to the placebo (low-dose, 18.6 l/min, P = 0.10; high-dose, 30.7 l/min, P = 0.001; placebo, 11.3 l/min). Similarly, PEF was improved at the end of the study after 20 weeks (low-dose 20.8 l/min, P = 0.046; high-dose, 29.9 l/min, P = 0.02; placebo, 10.2 l/min). FEV1 improvements were statistically not significant (low-dose, + 2.1%, P = 0.49; high-dose, + 1.9%, P = 0.81; placebo, + 1.0%) (59).

During the 20-week study period, 28% of patients in the low-dose anti-IgE group (P = 0.01) and 30% of patients in the high-dose anti-IgE group (P = 0.03) reported asthma exacerbation, compared with 45% of patients receiving the placebo, even though steroid use was reduced to a higher degree in the anti-IgE groups.

In summary, this study showed that anti-IgE improved asthma symptoms, reduced exacerbation rates and allowed the reduction of oral or inhaled steroid medication without requirement for increased rescue medication. Improvements by anti-IgE therapy were modest, but significantly better than in the placebo group, and occurred despite reductions in steroid and beta-2 agonist therapy. Anti-IgE antibodies were safe and tolerated without complains. These promising results stimulated succeeding studies with anti-IgE on a larger scale and with modified settings.

Effects of anti-IgE on asthma exacerbation (Phase III studies) Three identically designed large-scale phase III studies were performed to evaluate the efficacy of anti-IgE in the treatment of asthma: protocol 008 in the US (60), protocol 009 in the EU, US, South Africa and Australia (61), and protocol 010 in asthmatic children in the US (62). In contrast to the phase II study (59), anti-IgE was administered subcutaneously rather than intravenously and only once every 4 weeks for patients with low and intermediate IgE baseline serum levels. Duration of the trial was extended, and the age range of the adult patients increased; the primary endpoints now were frequency of asthma exacerbations. In contrast to the studies in adults, asthma was well controlled (not symptomatic) on entry to the study with children (62). Differences between anti-IgE and placebo-treated patients therefore were only obvious during the steroid-withdrawal phase.

Study design : Multi-centre, randomized, double-blind, parallel-group, placebo-controlled studies.

Patients : 523 (protocol 008) and 546 (protocol 009) adolescent and adult patients (12–75, mean 40 years) with moderate to severe asthma and requirements for daily ICS therapy; 334 children (protocol 010) (5–12, mean 9 years) with moderate to severe asthma and stable with daily ICS.

Primary outcome : Incidence and frequency of exacerbations (PEF < 50% of personal best, > 50% increase in beta-2-agonist use, FEV1 > 20% below baseline).

Secondary outcome : Symptom scores, FEV1, PEF, beta-2-agonist use.

Medication : Four phases: run-in period of 4 weeks to stabilize on therapy with beclomethasone (BDP) (adult patients had to be symptomatic), stable-phase with stable steroid medication for 16 weeks, steroid-withdrawal with tapering of steroid dosages by 25% every 2 weeks for 8 weeks and extension with stable lowest tolerated dose of BDP for the next 4 weeks, extension-period with continuation of placebo or anti-IgE therapy for 5 months. Anti-IgE was administered sc at a dose of 0.016 mg/kg body weight/IU total serum IgE, once every 4 weeks starting with the stable phase.

Results : The main findings of the Phase III trials were similar and confirmed the results of the Phase II trial ( 59 ). Treatment with anti-IgE was significantly more effective than the placebo in reducing the number of exacerbations, the primary endpoint of the trials, in both the stable-steroid and the steroid-withdrawal phase (Fig. 5). Mean number of exacerbations in the anti-IgE treatment group during the stable-steroid and the steroid-withdrawal phases were 58% and 52% lower, respectively (P < 0.001 for both) (60). This reduction in asthma exacerbations in the anti-IgE treatment group was obvious despite significantly lower use of ICS (126 µg/d BDP in the anti-IgE vs. 210 µg/d in the placebo group) or complete withdrawal of BDP (43% anti-IgE vs. 19% placebo, P < 0.001) during the steroid-withdrawal phase.

Symptom scores improved in both the placebo-treated and the anti-IgE treated patients, but the improvement was significantly higher in the latter group, despite the lower use of corticosteroids. Similar, beta-2-agonist use was significantly lower in the anti-IgE group than in the placebo group during the stable-steroid phase (Fig. 6). Lung function improved significantly more for patients receiving anti-IgE compared to the placebo, as indicated by increases in PEF (18.5 l/min vs. 6.9 l/min, P < 0.05) and a small, but significant, improvement in FEV1 (4.3% vs. 1.4%, P < 0.02).

In a similar way, treatment of asthmatic children with anti-IgE showed significantly better results than the placebo during the steroid withdrawal-phase for frequency and incidence of exacerbation (number of episodes per patient: 0.42 vs. 2.72, P < 0.001), median reduction of BDP doses (100% vs. 67%, P = 0.001), complete discontinuation of steroids (55% vs. 39% of patients, P = 0.004), and requirements for rescue medication (daily number of puffs: 0 vs. 0.46, P = 0.004). No statistical differences occurred for symptom scores or spirometry measurements (PEF) between the two groups in either the stable-steroid or the steroid-withdrawal phase (62).

Taken together, the phase III studies show that treatment of adults and children with moderate to severe asthma with anti-IgE is safe, statistically lowers the number of disease exacerbations and reduces the requirements for ICS use.

(4) Anti-IgE and Allergic Rhinitis

SAR is a frequently underestimated disease with regards to impairment of quality of life (QOL) of the patients, who experience a significant level of morbidity. Allergen avoidance as a means of secondary intervention is difficulty to achieve for patients with SAR, who are often sensitized to multiple outdoor allergens. So far, SIT is the only available curative approach (41, 63), but its application is restricted with regard to polyzensitized and very young patients. But especially the polysensitzed group of patients require therapy for several months of the year and suffer most from decreased QOL (64, 65) and reduced productivity at the school or in the working place (66). Despite optimized treatment regimens, including antihistamines, corticosteroids, or mast cell stabilizers, many patients with SAR still have suboptimal symptom control (67). Therefore, new treatment options targeting more specifically and early in the allergic cascade are desirable.

Efficacy of anti-IgE in treatment of SAR in adults (phase II study) A large-scale trial was performed to assess optimal dosing regimens and test the efficacy of anti-IgE for the treatment of SAR (55).

Study design : Double-blind, placebo-controlled, multi-centre study.

Patients : 240 adults (> 18 years) with ragweed-induced SAR.

Medication : Three active treatment (each n  = 60) and two placebo arms ( n  = 20 placebo sc, n  = 40 placebo iv). Patients in the active arms received one iv loading dose (day 0, 1 month before ragweed season), followed by anti-IgE doses (in mg/kg body weight) of 0.15 mg/kg sc, 0.15 mg/kg iv, or 0.5 mg/kg iv on days 7, 14, 28, 42, 56, 70, and 84, followed by a 42-day observation period.

Primary outcome : Average of daily symptom scores during season, and number of days that patients experience symptoms.

Secondary outcome : QOL (Juniper Rhinoconjunctivitis Quality-of-Life questionnaire and MOS 36-item short-form health survey (SF-36)).

Results : Anti-IgE decreased serum IgE levels in a dose- and baseline IgE-dependent fashion (Fig. 4), and specific IgE levels correlated significantly with symptom scores. In none of the treatment groups were IgE levels consistently decreased to less than 25 IU/ml. But only patients with IgE levels below detection level (< 25 IU/ml) experienced a marked reduction of symptoms, a group of patients too small ( n  = 11) to show significance. Moreover, the averaged symptom score before and during the peak of the season was only small (before season 0.6; during season 0.91 in placebo and 0.7–0.8 in anti-IgE groups, n.s.), and use of rescue medication was similar between the groups. Neither did QOL scores differ between the groups nor was specific skin test reactivity altered over the course of the study, with the exception of the high dose anti-IgE group, which had a marginally significant increase in average end-point titration concentration.

These data showed that (i) clinical efficacy is only achieved in patients with significantly reduced IgE levels, and (ii) higher doses of anti-IgE are required for significant suppression of IgE levels. This resulted in a dosing regimen taking individual body weight and basic IgE levels into account: 0.005 mg anti-IgE/kg body weight/week for each IU baseline IgE/ml serum, doses between 150 and 375 mg per application period of 2 or 4 weeks. Because equivalent results were seen with iv and sc dosing regimens, the latter was preferred in consecutive trials for practical reasons.

Effects of anti-IgE on symptom scores in SAR in adults (phase III study) The results of the previous study (55) warranted further evaluation of the efficacy of anti-IgE therapy in SAR, utilizing higher anti-IgE doses (68).

Study design : Randomized, double-blind, placebo-controlled, parallel group, multi-centre study.

Patients : 251 randomized adults (17–66 years) with moderate-to-severe SAR to birch pollen (history ≥  2 years, positive specific skin test, baseline serum IgE 30–700 IU/ml).

Medication : 300 mg of anti-IgE ( n  = 164) or placebo ( n  = 86) administered sc during the birch pollen season depending on baseline IgE levels (≤ 150 IU/ml at weeks 0 and 4, ≥ 150 IU/ml weeks 0, 3 and 6).

Primary outcome : Average daily nasal symptom severity score (seven symptoms, 4-point scale).

Secondary outcome : Number of rescue antihistamine tablets per day, the proportion of days with any SAR medication use, and rhinoconjunctivitis-specific quality of life (QOL).

Results : Free serum IgE levels at weeks 3/4 were decreased to less than 25 IU/ml in 113 (69%) of subjects treated with anti-IgE, and exceeded 50 IU/ml only in three of these patients. A better clinical outcome was significantly correlated with free IgE levels below 25 IU/ml. In the placebo group, free IgE levels at weeks 3/4 exceeded 50 ng/ml in all but one subject. Average daily nasal symptom severity did not change during the course of the study in the anti-IgE group (0.71 at baseline vs. 0.70 total average during study), but increased in the placebo group (0.78 vs. 0.98, P  < 0.001). Ocular symptom severity scores decreased from 0.47 to 0.43 in anti-IgE treated patients, but increased from 0.43 to 0.54 in the placebo group ( P  = 0.031). Importantly, the average use of rescue medication was significantly lower in the anti-IgE group than in the placebo group (0.59 vs. 1.37 tablets per day, P  < 0.001), and the proportion of days on which no SAR medication was required was almost twice as high (49% vs. 28%, P  < 0.001). Statistically significant differences in favour of anti-IgE were similarly observed for estimation of QOL (activities, nasal symptoms, non nose–eye symptoms and practical problems). Patients' evaluation of efficacy of treatment was in favour of anti-IgE treatment ( P  = 0.001). Twenty-one percent of verum treated patients reported complete control of symptoms (vs. 2% of placebo treated), 59% estimated improvement (vs. 35%), and only 2% experienced worsening (vs. 13%) ( 68 ).

Conclusively, anti-IgE was safe and effective in controlling birch pollen-induced SAR compared with the placebo, with less use of rescue medication and improved QOL. The rather shallow effect of anti-IgE treatment may be explained by an unexpected early pollen season during that specific year of the trial in Scandinavia, which resulted in the beginning of anti-IgE treatment less than 1 week in advance of the first pollen exposure in more than 50% of all patients.

Anti-IgE in combination with SIT in children with SAR (Phase III study) SIT is considered as the only curative treatment for SAR and allergic asthma, as long as its prerequisites are fulfilled: small scale of sensitizations, and administration of adequate doses of standardized allergens (42, 69). Beneficial effects of SIT can be observed even years after discontinuation (70, 71). Especially in children, administration of SIT may prevent the extension of upper airway disease to the lower airways. However, SIT carries the risk of serious side-effects, such as anaphylactic reactions. Since anti-IgE reduces the serum concentration of IgE and thereby reduces IgE-mediated reactions, it was hypothesized that concomitant treatment of anti-IgE and SIT could improve the risk/benefit ratio of SIT in polyzensitized patients during the consecutive pollen seasons and thereby would prove clinically superior to treatment with SIT alone. Therefore, a study in children with SAR was initiated to investigate whether combined therapy with SIT and anti-IgE is preferable to single treatment alone (72).

Study design : Randomized, double-blind, parallel-group, multi-centre study.

Patients : 221 patients (6–17 years) with moderate-to-severe SAR and sensitization to birch- and grass-pollen (history ≥  2 years, IgE specific to birch and grass CAP class ≥  2, total serum IgE levels 30–1300 IU/ml).

Medication : Four treatment arms: each subject was started on SIT-birch (two groups) or SIT-grass (two groups) for ≥ 14 weeks prior to start of birch-pollen season (Build up phase: 12 injections, 1-week intervals. Maintenance phase: five injections, 4-week intervals). After SIT titration (12 weeks), placebo or anti-IgE was added for 24 weeks to either one of the two groups of the respective SIT arms. When analysed separately by season, the two groups receiving unrelated SIT were considered as placebo controls. Anti-IgE was administered sc at 2- or 4-week intervals at a dose equivalent to a minimum of 0.016 mg/kg/IU IgE/ml serum in 4 weeks.

Primary outcome : Symptom load (sum of mean daily symptom severity score plus mean daily rescue medication use).

Secondary outcome : Rescue medication: topical levocabastine (eyedrops, nasal spray), inhaled salbutamol, cetirizine and prednisolone.

Results : Combination therapy of anti-IgE and SIT reduced symptom load over the entire pollen seasons (birch and grass) by 48% compared to SIT alone ( P  < 0.001). Reduction was highly significant for both analyses, SIT-birch + anti-IgE vs. SIT-birch + placebo, and for SIT-grass + anti-IgE vs. SIT-grass + placebo (Fig. 7).

In the birch pollen season, the addition of anti-IgE to the relevant SIT-birch reduced symptom load by 50% compared to SIT alone (median symptom score 0.46 vs. 0.23, P = 0.003). Anti-IgE reduced symptom load in comparison with the irrelevant SIT-grass alone by 39% (0.44 vs. 0.27, P = 0.1). Unexpectedly, the patients treated with SIT-birch (+ placebo) alone showed a comparable symptom load of 0.46 vs. 0.44 (P = 0.43) compared with the group treated with SIT-grass (+ placebo). This may be caused by pollen exposure before adequate cumulative SIT doses were administered and may also reflect the very modest symptom load scores in this group.

In the grass pollen season, the relevant SIT-grass reduced symptom load by 32% compared to irrelevant SIT-birch + placebo (0.61 vs. 0.89, P = 0.1). The addition of anti-IgE to the relevant SIT-grass had a highly significant effect with 57% decrease in mean symptom load compared to SIT-grass alone (0.26 vs. 0.61, P = 0.001). Addition of anti-IgE to the unrelated SIT-birch (considered as treatment with anti-IgE alone) reduced symptom load by 45% compared with unrelated SIT-birch alone (0.49 vs. 0.89, P < 0.001) (72).

Differentiating the two components adding to symptom load revealed that rescue medication reduction was a major contributing factor to the observed improvements. Over both pollen seasons, addition of omalizmab resulted in reduction of the median rescue medication score of 78% compared to SIT-birch groups (0.06 vs. 0.27; P < 0.001) and by as much as 81% compared to SIT-grass groups (0.03 vs. 0.16; P = 0.001). Oral corticosteroids as the last rescue medication to be used were reported by 15 patients receiving SIT + placebo compared to five patients on SIT + anti-IgE. Symptom severity, the second component of symptom load, was significantly reduced by the addition of anti-IgE in the separate SIT groups (0.24 vs. 0.40; P < 0.001).

The results of the study strongly support the primary hypothesis, that combined treatment with SIT and anti-IgE is more effective than SIT alone. Patients receiving anti-IgE required almost no additional rhinitis medication.

In comparison to the study on SAR in adults (68), where 44% of patients were recruited less than 1 week and 10% of patients were recruited even after the start of the unexpectedly early pollen season, in the study in children, anti-IgE was already administered 45 days prior to the start of the birch pollen season. The main requirements for successful anti-IgE therapy of patients with SAR therefore may be concluded from the three SAR trials: (i) the dose regimen has to be adopted to personal body weight and IgE base levels; (ii) free IgE serum levels have to be reduced substantially; and (iii) start of the anti-IgE treatment has to be early enough and far enough in advance of the pollen season/allergen exposure.

III. Conclusion

The advanced understanding of the pathophysiological mechanisms underlying the development of allergic diseases such as asthma has promoted several new immunological approaches towards a novel mode of therapy. They tend not to act just as unspecific anti-inflammatory drugs reducing the ongoing allergic response, but rather to stop the development of allergic diseases by a specific, curative approach. The first line of these immunomodulatory regimens has now passed initial evaluations in clinical trials, and results are not always favourable (73, 74). The conclusion one may draw from these study results is that the clinical situation of asthma in humans is clearly more complex than the experimental situation in animal models (75, 76). Simply targeting one single cellular or molecular mediator or pathway may not be sufficient to cope with the complex and redundant inflammatory process involved in the development of human asthma (77).

The most advanced of the novel therapeutic approaches is treatment with anti-IgE antibodies (anti-IgE). Targeting IgE aims at the common and most distinct phenotype obvious in all patients suffering from allergic diseases: increased IgE serum levels. There are quite a lot of evidential data demonstrating a pivotal role for IgE in the development of bronchial asthma: increased IgE serum levels are associated with prevalence rates and disease severity (31, 32), asthma in children is almost always associated with production of allergen-specific IgE and positive skin test reactivity against environmental allergens (8, 31), and even in patients with non-allergic asthma, despite normal IgE serum levels, an extensive production of IgE in large areas of the airways has been found (36). On the other hand, experimental data from murine models demonstrate that development of airway inflammation and hyperreactivity to unspecific stimuli, two of the three main features of the disease, may occur independently of B cells (78), IgE-production (78, 79) or IgE-mediated mast-cell activation (80). Concordantly, in animals with a robust allergen-mediated inflammatory response of the airways, treatment with anti-IgE antibodies does not inhibit development of airway inflammation or hyperreactivity (81).

The findings of clinical phase II and III trials with anti-IgE antibody treatment in asthmatic patients show that anti-IgE is an effective therapy for moderate to severe allergic asthma: it reduces frequency of exacerbations, improves symptom scores and reduces the requirements for steroid medication, very important especially for consideration of future treatment strategies for childhood asthma. Similarly important, it is safe and well tolerated. Some of the improvements in symptom scores, exacerbation rates and lung function data during the course of the trials were also seen in the placebo-treated group, presumably demonstrating the benefits of continuous physician monitoring, but differences between the anti-IgE and the placebo-treated group reached significance for almost all important endpoints in favour for anti-IgE. Conclusively, the results show that anti-IgE is efficacious and safe for treatment of asthma.

The situation for SAR appears to be less complicated. SAR clearly is a mainly IgE-mediated disease, in which chronic inflammation and remodelling of anatomical structures are not as important as in asthma. The immediate hypersensitivity reaction to environmental allergens, triggered by allergen-specific IgE and IgE-mediated mast cell activation, is the basic pathophysiological correlate to the symptoms apparent in patients with SAR. Thus, targeting IgE is a plausible way of preventive therapy for SAR.

Clinical phase II and III trials investigating safety and efficacy of anti-IgE for treatment of SAR demonstrated that anti-IgE effectively reduces free serum IgE levels and allergen-related symptoms, and increases QOL. Moreover, anti-IgE is not allergen-specific and thus adds to the beneficial effects of SIT, a very significant improvement for the often multisensitized SAR patients, who suffer under long pollen seasons and frequent co-morbidity of the lower airways. In contrast to SIT, anti-IgE has the drawback that its effect may be transient, but the advantage that it is not allergen specific. Even more important, treatment with anti-IgE antibodies may help to zprevent the “allergic march”, the development of allergen-mediated airway diseases such as bronchial asthma in patients with predisposing SAR. Effective control of SAR thus may provide preventive and/or therapeutic treatment of concomitant respiratory diseases.

Future trials have to examine the efficacy of anti-IgE in comparison with standard medication for treatment of allergic diseases, and cost-related analysis of the advantages of anti-IgE treatment has to be performed. New areas of potential indications for anti-IgE have to be investigated, especially those where IgE plays a major role for development of the disease. Food allergies in infancy require expensive diets, insect-venom-allergic patients are in risk of anaphylactic reactions, side-effects during (rush) SIT are a major safety issue, and severe atopic dermatitis is often associated with high IgE serum levels. Here, anti-IgE may be a very valuable and even cost-reducing addition to standard therapies. Finally, future trials have to delineate predictors for “responders” vs. “non-responders”. This will help to outline the optimal target group of patients that may ideally benefit from anti-IgE therapy.

Ancillary